Accumulating evidence is establishing a series of less traditional risk factors as being critical for hypertension, cardiovascular disease and stroke. These factors include obstructive sleep apnea, impaired endothelial function, high central blood pressure and aortic stiffness. Furthermore, they are each associated with type 2 diabetes and its complications. The emergence of these non-traditional risk factors provides key physiologic targets where understanding the biological underpinnings could have substantial impact on developing strategies for disease prevention and/or slowing the progression of several chronic conditions. Each of these factors is known to have a substantial genetic component. Consequently, coupling appropriate measures of each in the context of a genome-wide association study has immense potential for elucidating those genes and pathways whose genetic variation mediates differences in risk factor levels and subsequently disease. Accordingly, we propose to measure this axis of non-traditional risk factors in 1,200 previously characterized Mexican Americans from Starr County, Texas, for whom we will already have genotyping from the Affymetrix Human Genome-Wide SNP Array 6.0 platform. This work builds on our 28 years of experience investigating the genetics and epidemiology of type 2 diabetes, its complications, and related conditions in Starr County. Specifically, we propose: 1) to determine the contribution of genetic variation to obstructive sleep apnea, impaired endothelial function, central blood pressure, aortic stiffness and their profile; 2) to determine whether type 2 diabetes and pre-diabetes mediate genomic associations with this axis of non-traditional risk factors; 3) to replicate significant results through collaboration with other groups including the Hispanic Health Cohort; and 4) to distinguish causal polymorphisms from those simply in linkage disequilibrium for identified genes through deep re-sequencing and analyses that exploit network theory and evolutionary contexts. There is a paucity of epidemiologic data for this axis of risk factors in the Hispanic population in general. Furthermore, genome-wide association studies of these risk factors in any population have not yet been conducted to any significant extent. Such studies have proven to be remarkably effective in identifying genes not previously implicated in chronic disease risk potentially opening new pathways for intervention. We expect our proposed study to do the same for this set of non-traditional risk factors. They are particularly attractive given their physiologic interrelatedness and their consistent associations with the constellation of diseases most responsible for the morbidity and mortality burden borne by most populations. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea, impaired endothelial function, high central blood pressure and aortic stiffness are increasingly being shown as risk factors for the constellation of diseases most responsible for the morbidity and mortality burden borne by most populations. We propose to systematically evaluate the human genome for genetic variation that alters the levels of these factors and their relationships. These studies should identify genes not previously implicated in chronic disease risk potentially opening new pathways for intervention.